title: Combination therapy with a dipeptidyl peptidase-4 inhibitor and a proton pump inhibitor induces β-cell neogenesis from adult human pancreatic duct cells implanted in immunodeficient mice.
abstract: Combination therapy with a dipeptidyl peptidase-4 inhibitor (DPP-4i) and a proton pump inhibitor (PPI) raises endogenous levels of GLP-1 and gastrin, respectively, and restores pancreatic β-cell mass and normoglycemia in nonobese diabetic (NOD) mice with autoimmune diabetes. The  aim of this study was to determine whether a DPP-4i and PPI combination could increase β-cell mass in the adult human pancreas. Pancreatic cells from adult human pancreas donors were implanted in NOD-severe combined immunodeficient (NOD-scid) mice and the mice were treated with a DPP-4i  and a PPI for 16 weeks. Human grafts were examined for insulin content and insulin-stained cells. Graft β-cell function was assessed by intravenous glucose tolerance tests (IVGTT) and by glucose control in human cell-engrafted mice treated with streptozotocin (STZ) to delete mouse pancreatic  β-cells. Plasma GLP-1 and gastrin levels were raised to two- to threefold in DPP-4i- and PPI-treated mice. Insulin content and insulin-stained cells in human pancreatic cell grafts were increased 9- to 13-fold in DPP-4i and PPI-treated mice and insulin-stained cells were colocalized with  pancreatic exocrine duct cells. Plasma human C-peptide responses to IVGTT were significantly higher and STZ-induced hyperglycemia was more completely prevented in DPP-4i- and PPI-treated mice with grafts than in vehicle-treated mice with grafts. In conclusion, DPP-4i and PPI combination therapy  raises endogenous levels of GLP-1 and gastrin and greatly expands the functional β-cell mass in adult human pancreatic cells implanted in immunodeficient mice, largely from pancreatic duct cells. This suggests that a DPP-4i and PPI combination treatment may provide a pharmacologic therapy  to correct the β-cell deficit in type 1 diabetes.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Suarez-Pinzon
authors.forename: Alex
authors.initials: A
authors.lastname: Rabinovitch
mesh_terms: D000328:Adult; D000818:Animals; D017690:Cell Transplantation; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D038081:Organogenesis / Q000187:drug effects*; D010183:Pancreatic Ducts / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D054328:Proton Pump Inhibitors